A Genome-Wide Scan Identifies Variants in NFIB Associated with Metastasis in Patients with Osteosarcoma.
A Genome-Wide Scan Identifies Variants in NFIB Associated with Metastasis in Patients with Osteosarcoma.
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DOI：
10.1158/2159-8290.cd-15-0125
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发表时间：
2015-09
期刊：
影响因子：
28.2
通讯作者：
Savage SA
中科院分区：
文献类型：
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作者：
Mirabello L;Koster R;Moriarity BS;Spector LG;Meltzer PS;Gary J;Machiela MJ;Pankratz N;Panagiotou OA;Largaespada D;Wang Z;Gastier-Foster JM;Gorlick R;Khanna C;de Toledo SR;Petrilli AS;Patiño-Garcia A;Sierrasesúmaga L;Lecanda F;Andrulis IL;Wunder JS;Gokgoz N;Serra M;Hattinger C;Picci P;Scotlandi K;Flanagan AM;Tirabosco R;Amary MF;Halai D;Ballinger ML;Thomas DM;Davis S;Barkauskas DA;Marina N;Helman L;Otto GM;Becklin KL;Wolf NK;Weg MT;Tucker M;Wacholder S;Fraumeni JF Jr;Caporaso NE;Boland JF;Hicks BD;Vogt A;Burdett L;Yeager M;Hoover RN;Chanock SJ;Savage SA
骨肉瘤是儿童最常见的骨恶性肿瘤，转移是其死亡的主要原因。我们对935例骨肉瘤患者进行了诊断时骨肉瘤转移的多阶段全基因组关联研究，以确定种系遗传变异是否与转移风险有关。我们在NFIB中发现了一个SNP rs7034162，该SNP与欧洲骨肉瘤病例以及非洲和巴西血统病例的转移显著相关（所有病例的荟萃分析：P=1.2×10−9,OR 2.43, 95% CI 1.83-3.24）。风险等位基因与NFIB表达降低显著相关，NFIB表达降低导致骨肉瘤细胞迁移、增殖和集落形成增加。此外，在小鼠中进行转座子筛选，发现了大量在Nfib中含有失活插入的骨肉瘤，并降低了Nfib的表达。这些数据表明rs7034162的种系遗传变异在骨肉瘤转移中很重要，NFIB是骨肉瘤转移的易感基因。
Metastasis is the leading cause of death in osteosarcoma patients, the most common pediatric bone malignancy. We conducted a multi-stage genome-wide association study of osteosarcoma metastasis at diagnosis in 935 osteosarcoma patients to determine whether germline genetic variation contributes to risk of metastasis. We identified a SNP, rs7034162, in NFIB significantly associated with metastasis in European osteosarcoma cases, as well as in cases of African and Brazilian ancestry (meta-analysis of all cases: P=1.2×10−9, OR 2.43, 95% CI 1.83–3.24). The risk allele was significantly associated with lowered NFIB expression, which led to increased osteosarcoma cell migration, proliferation, and colony formation. Additionally, a transposon screen in mice identified a significant proportion of osteosarcomas harboring inactivating insertions in Nfib, and had lowered Nfib expression. These data suggest that germline genetic variation at rs7034162 is important in osteosarcoma metastasis, and that NFIB is an osteosarcoma metastasis susceptibility gene.